The overall goal of this project is to identify potent and specific small molecular inhibitors of the protein tyrosine kinase (PTK) pp60c-src. This goal will be accomplished by the synthesis and biological evaluation of focused libraries based upon the 1,4-benzodiazepine and beta-turn mimetic frameworks. The libraries based upon the 1,4=-benzodiazepine framework will be designed to optimize both the affinity and specificity of lead compounds identified by screening an initial library of 1680 1,4- benzodiazepine derivatives. As described in the best inhibitors at 30-40 muM (assays performed aat saturating ATP concentrations, 0.2 mM). Dr. Gary Gallick has determined that selected benzodiazepine lead compounds were not cytotoxic to AFB-13 normal human fibroblasts, yet inhibited the growth of HT-29 colon tumor cells. These results indicate that these compounds are worthwhile leads for further optimization. As more structural information on the cyclic peptide inhibitors developed by John McMuray becomes available, we will also utilize this information for further interactions of benzodiazepine sub-library synthesis and optimization. The libraries that are based upon the beta-turn mimetic framework will be designed based upon the extensive structure activity studies that have been performed by John McMurray on cyclic peptide derivatives. Although the exact conformations of the cyclic peptide inhibitors have not yet been completely determined, sufficient information is available for the preparation and screening of focused libraries of turn mimetics.